Thrombosis remains a significant barrier to the development and implementation of blood-contacting medical devices. Contact activation of the blood plasma coagulation cascade has been shown to be a significant contributor to poor hemocompatibility of materials that leads to thrombosis. It is found that that hydrophilic materials are very efficient activators of plasma coagulation whereas hydrophobic materials are relatively inefficient activators. Classical biochemistry attributes this observation to the preferential adsorption/ assembly of activator-complex proteins directly onto hydrophilic surfaces. However, this explantion is inconsistent with the experimental finding that proteins do not adsorb to hydrophilic surfaces but do adsorb to hydrophobic surfaces. An objective of this proposal is to remedy this apparent inconsistency by testing the hypothesis that "Hydrophobic procoagulant surfaces are inhibitory to activation of the intrinsic pathway of the plasma coagulation cascade. Hydrophilic procoagulant surfaces are the most efficient activators because protein adsorption to these surfaces does not compete with solution-phase assembly of AC proteins, whereas contact activation by relatively hydrophobic procoagulants is moderated by adsorption of AC proteins directly onto these surfaces, leading to decreased activation." This proposed biochemistry is different than the conventional mechanism because it views hydrophobic surfaces as inhibitory to plasma activation rather than activation being specific to hydrophilic (anionic) surfaces, and therefore resolves the apparent inconsistentencies with observed protein adsorption behavior. This hypothesis is tested through three specific aims that utilize surface-science techniques and experimental/theoretical analysis of enzyme activation to understand relationships among protein adsorption, activation of the activation complex proteins, and subsequent production of FXIa. This information is critical to the prospective bioengineering of materials with improved hemocompatibility for a wide variety of cardiovascular devices. Lay description: Formation of blood clots on materials used in medical devices is a problem. The reasons for clot formation are unclear, and seemingly contradict what is already known about how blood responds to materials. This proposal seeks to understand the reasons for clot formation on materials by measuring the interaction of blood components with materials and how those components change in response.